Article

Better understanding of mechanisms of schizophrenia and bipolar disorder: from human gene expression profiles to mouse models.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Neurobiology of Disease (Impact Factor: 5.2). 09/2011; 45(1):48-56. DOI: 10.1016/j.nbd.2011.08.025
Source: PubMed

ABSTRACT The molecular mechanisms of major mental illnesses, such as schizophrenia and bipolar disorder, are unclear. To address this fundamental question, many groups have studied molecular expression profiles in postmortem brains and other tissues from patients compared with those from normal controls. Development of unbiased high-throughput approaches, such as microarray, RNA-seq, and proteomics, have supported and facilitated this endeavor. In addition to genes directly involved in neuron/glia signaling, especially those encoding for synaptic proteins, genes for metabolic cascades are differentially expressed in the brains of patients with schizophrenia and bipolar disorder, compared with those from normal controls in DNA microarray studies. Here we propose the importance and usefulness of genetic mouse models in which such differentially expressed molecules are modulated. These animal models allow us to dissect the mechanisms of how such molecular changes in patient brains may play a role in neuronal circuitries and overall behavioral phenotypes. We also point out that models in which the metabolic genes are modified are obviously untested from mental illness viewpoints, suggesting the potential to re-address these models with behavioral assays and neurochemical assessments.

1 Follower
 · 
102 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent evidence implicates glutamatergic synapses as key pathogenic sites in psychiatric disorders. Common and rare variants in the ANK3 gene, encod-ing ankyrin-G, have been associated with bipolar dis-order, schizophrenia, and autism. Here we demon-strate that ankyrin-G is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology. Using superresolution microscopy we find that ankyrin-G forms distinct nanodomain struc-tures within the spine head and neck. At these sites, it modulates mushroom spine structure and function, probably as a perisynaptic scaffold and barrier within the spine neck. Neuronal activity promotes ankyrin-G accumulation in distinct spine subdomains, where it differentially regulates NMDA receptor-dependent plasticity. These data implicate subsynaptic nanodo-mains containing a major psychiatric risk molecule, ankyrin-G, as having location-specific functions and open directions for basic and translational investiga-tion of psychiatric risk molecules. INTRODUCTION
    Neuron 10/2014; 84(2). DOI:10.1016/j.neuron.2014.10.010 · 15.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as 'models of schizophrenia' but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms.Molecular Psychiatry advance online publication, 16 September 2014; doi:10.1038/mp.2014.91.
    Molecular Psychiatry 09/2014; 19(10). DOI:10.1038/mp.2014.91 · 15.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia (SZ) and bipolar disorder (BD) are severe psychiatric conditions with a neurodevelopmental component. Genetic findings indicate the existence of an overlap in genetic susceptibility across the disorders. Also, image studies provide evidence for a shared neurobiological basis, contributing to a dimensional diagnostic approach. This study aimed to identify the molecular mechanisms that differentiate SZ and BD patients from health controls but also that distinguish both from health individuals. Comparison of gene expression profiling in post-mortem brains of both disorders and health controls (30 cases), followed by a further comparison between 29 BD and 29 SZ revealed 28 differentially expressed genes. These genes were used in co-expression analysesthat revealed the pairs CCR1/SERPINA1, CCR5/HCST, C1QA/CD68, CCR5/S100A11 and SERPINA1/TLR1 as presenting the most significant difference in co-expression between SZ and BD. Next, a protein-protein interaction (PPI) network using the 28 differentially expressed genes as seeds revealed CASP4, TYROBP, CCR1, SERPINA1, CCR5 and C1QA as having a central role in the diseases manifestation. Both co-expression and network topological analyses pointed to genes related to microglia functions. Based on this data, we suggest that differences between SZ and BP are due to genes involved with response to stimulus, defense response, immune system process and response to stress biological processes, all having a role in the communication of environmental factors to the cells and associated to microglia. Copyright © 2014 Elsevier B.V. All rights reserved.
    Schizophrenia Research 12/2014; 161(2-3). DOI:10.1016/j.schres.2014.10.055 · 4.43 Impact Factor

Full-text (2 Sources)

Download
33 Downloads
Available from
Jun 5, 2014